My long term goal is to pursue a career in Academic Pediatrics which combines laboratory research and clinical activities in Hematology and Transfusion medicine. My initial exposure to laboratory research was a yearlong project during Medical School. After training in Pediatrics, I entered the Hematology-Oncology Fellowship at the Children's Hospital of Philadelphia, which I combined with a fellowship in Blood Banking and Transfusion medicine at the Hospital of th University of pennsylvania. My laboratory research was focused on a human model system of cold agglutinin autoimmune hemolytic anemia associated with a B cell lymphoma. The significance of this work lay in the demonstration, based on immunoglobulin gene analysis, that antigen driven clonal selection might play a role in th pathogenesis of the lymphoma. i have since pursued laboratory projects addressing aspects of clonal selection and V gene use in human autoantibodies, such as cold agglutinins, and in B cell neoplasms such as B-CLL and immunodeficiency related lymphomas. i started as Assistant Professor of Pediatrics at Children's Hospital in July 1992. Through this award, I hope to gain the independence and scientific recognition needed to establish a laboratory research program in molecular immunology which will complement and enhance my clinical activities. The proposed research addresses the role of antigen or ligand mediated selection in the formation and expression of the immunoglobulin VH gene repertoire during normal development. The goal is to determine if there is restriction of the VH gene repertoire in normal peripheral B cell and bone marrow pre-B cell compartments, and how such patterns of restriction change with development. The approach will be to prepare unbiased libraries of VH genes from defined B cell populations in umbilical cord blood an later in development, and to evaluate these libraries by a combination of screening with oligonucleotide probes and selective sequencing to identify individual VH gene segments. The results of these studies will have their greatest significance in the interpretation of the apparent VH gene restriction observed in disease states, such as B cell neoplasms and autoimmunity, and perhaps in immunodeficiencies. The sponsor, Dr. leslie Siberstein, is an established investigator in molecular genetic approaches to human autoimmune disease, specifically cold agglutinin disease, and to human B cell neoplasia. His laboratory is an ideal environment in which to pursue the proposed research, receive informed criticism, and ultimately develop an independent research program. The co-sponsor, Dr. Richard Hardy, is a leading figure in B cell immunology whose expertise in B cell development and in flow cytometry will be of enormous benefit to my project. my position at the Children's Hospital of Philadelphia will provide access to necessary clinical specimens and to the resources of the Division of Hematology and the Department of Pathology which have made commitments to support the development of my career as a physician-scientist.